Sphingosine-1-phosphate (S1P) was considered to be merely an intermediary metabolite in sphingosine metabolism. However, it has been reported that S1P has a cell growth promoting action and a control action of a cell motility function, and it is now clear that S1P is a new lipid mediator that exhibits various physiological actions, such as an apoptosis action, a cell morphology regulation action, and vasoconstriction (Non-Patent Literatures 1 and 2).
This S1P combines two actions, an action as an intracellular second messenger and an action as an intercellular mediator. Studies into S1P's action as an intercellular mediator are especially active. It has been reported that information is transmitted via a plurality of G protein-coupled receptors present on the cell membrane surface (Endothelial Differentiation Gene, EDG) (Non-Patent Literatures 1 and 3). Currently, five sub-types of S1P receptors are known, including Edg-1, Edg-3, Edg-5, Edg-6, and Edg-8 which are called as S1P1, S1P3, S1P2, S1P4, and S1P5, respectively.
From various studies into these S1P receptors, it has been reported that so-called S1P receptor regulator, which exhibits an agonistic or antagonistic action against this receptor, is effective against a wide range of diseases. Patent Literature 2 and Non-Patent Literatures 4 to 7 report that the S1P3 antagonist is effective as a therapeutic or preventive medicine for respiratory tract contraction, bronchial asthma, chronic obstructive pulmonary disease (COPD), pulmonary emphysema, tracheal stenosis, diffuse panbronchiolitis, bronchitis resulting from infection, connective tissue disease, or transplantation, diffuse pulmonary hamartoangiomyomatosis, adult respiratory distress syndrome (ARDS), interstitial pneumonitis, lung cancer, pneumonia hypersensitivity, idiopathic interstitial pneumonia, fibrosis of the lung, sepsis, or cytokine storm caused by an influenza virus or RS virus infection.
Further, Patent Literatures 3 to 6 show that the S1P3 antagonist is also effective against arterial sclerosis, blood vessel intimal hypertrophy, solid tumors, diabetic retinopathy, rheumatoid arthritis, cardiac arrest, ischemia-reperfusion disorders, cerebral blood vessel spasms after subarachnoid bleeding, angina pectoris or myocardial infarction caused by coronary vessel spasms, glomerulonephritis, thrombosis, lung disease caused by pulmonary edema such as ARDS, cardiac arrhythmia, eye disease, eye hypertension, glaucoma, glaucomatous retinopathy, optic neuropathy, macula-lutea degeneration and the like.
Further, although currently there are recombinants form of human activated protein C (rhAPC) in medicines that are effective as sepsis therapeutic medicines, rhAPC may also cause hemorrhaging as a side effect. Therefore, there is a need to develop a novel sepsis therapeutic or preventive medicine that does not exhibit such side effects. Non-Patent Literatures 5 and 7 report that the S1P3 receptor contributes to multiple organ failure caused by sepsis based on analysis using S1P3 knockout mice, thereby suggesting that the S1P3 antagonist may be effective as a sepsis therapeutic or preventive medicine. In addition, it has been reported that the S1P1 antagonist increases vascular wall permeability, and causes pulmonary edema (Non-Patent Literature 8). Therefore, in order for a novel sepsis therapeutic or preventive medicine to have a high level of safety, that therapeutic or preventive medicine should have a weak S1P1 antagonistic action, preferably exhibit an S1P1 agonistic action, and more preferably not exhibit an action against the S1P1 receptor.
Known S1P receptor regulators include, for example, the compounds represented by the following general formula (A) described in Patent Literature 1,
(In the formula (A), R1 represents a hydrogen atom, a halogen atom, a halogenated or unhalogenated lower alkyl group having 1 to 4 carbon atoms, a hydroxy group, a phenyl group, an aralkyl group, a lower alkoxy group having 1 to 4 carbon atoms, a trifluoromethyloxy group, an optionally substituted aralkyloxy group, an optionally substituted phenoxy group, a cyclohexylmethyloxy group, an optionally substituted aralkyloxy group, a pyridylmethyloxy group, a cinnamyloxy group, a naphthylmethyloxy group, a phenoxymethyl group, a hydroxymethyl group, a hydroxyethyl group, a lower alkylthio group having 1 to 4 carbon atoms, a lower alkylsulfinyl group having 1 to 4 carbon atoms, a lower alkylsulfonyl group having 1 to 4 carbon atoms, a benzylthio group, an acetyl group, a nitro group, or a cyano group; R2 represents a hydrogen atom, a halogen atom, a halogenated or unhalogenated lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, an aralkyl group, or an aralkyloxy group; R3 represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a benzyloxy group, a phenyl group, a lower alkoxymethyl group having 1 to 4 carbon atoms or a lower alkylthio group having 1 to 4 carbon atoms; R4 represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxymethyl group having 1 to 4 carbon atoms, a lower alkylthiomethyl group having 1 to 4 carbon atoms, a hydroxymethyl group, a phenyl group, or an aralkyl group; R5 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms; X represents O, S, SO, or SO2; and Y represents —CH2O—, —CH2-, —CH═CH—, —CF═CF—, —CH2CH2-, —CH2CFH—, —CH2CF2-, or —CH(OH)CF2-.).
However, Patent Literature 1 does not include 2-aminophosphoric acid monoester derivatives or 3-aminophosphonic acid derivatives having a diphenyl sulfide skeleton in which a hydroxyl group is substituted for a phenyl group. Further, the fact that 2-aminophosphoric acid monoester derivatives or 3-aminophosphonic acid derivatives having such a structure exhibit an excellent S1P3 receptor-antagonistic action is also not known.
Other examples of known S1P receptor regulators include the compounds represented by the following general formula (B) in Patent Literature 6,
(In the formula (B), R1 represents a chlorine atom, a linear alkyl group having 1 to 3 carbon atoms, or a trifluoromethyl group; R2 represents a fluorine atom or a chlorine atom; R3 represents a linear alkyl group having 1 to 3 carbon atoms; X represents an oxygen atom or a sulfur atom; and n denotes an integer of 2 or 3.).
Further, among the compounds represented by the general formula (B), it has been reported that the optically active compounds represented by the general formula (Ba), have a weak S1P3 agonistic action and an excellent agonistic action against S1P1 and/or S1P4.
(In the formula (Ba), R1, R3, and X are as defined above.)
However, the compounds having an inverse asymmetric center to the optically active compounds represented by the general formula (Ba), are not known. Further, the fact that such optically active compounds exhibit an excellent S1P3 receptor-antagonistic action is also not known.    Patent Literature 1 WO04074297 pamphlet    Patent Literature 2 WO03020313 pamphlet    Patent Literature 3 Japanese Patent Application Laid-Open No. 2005-247691    Patent Literature 4 WO07043568 pamphlet    Patent Literature 5 WO06063033 pamphlet    Patent Literature 6 WO08018427 pamphlet    Non-Patent Literature 1 Y. Takuma et al., Mol. Cell. Endocrinol., 177, 3 (2001).    Non-Patent Literature 2 Y. Igarashi, Ann, N.Y. Acad. Sci., 845, 19 (1998).    Non-Patent Literature 3 H. Okazaki et al., Biochem. Biophs. Res. Commun., 190, 1104 (1993).    Non-Patent Literature 4 Y. Gon et. al., Proc Natl Acad Sci USA. 102(26), 9270 (2005).    Non-Patent Literature 5 F. Nissen et al., Nature, 452, 654 (2008)    Non-Patent Literature 6 D. Christina et al., Am. J. Pathol., 170(1), 281 (2007)    Non-Patent Literature 7 F. Nissen et al., Blood, 113(12), 2859 (2009)    Non-Patent Literature 8 M. G. Sanna et al., Nature Chemical biology, 2, 434 (2006)